Table 2.

Potential factors that may cause resistance to trastuzumab emtansine

Factors decreasing intracellular DM1 level
T-DM1 binding to HER2	Low cancer HER2 expression
	HER2 down-regulation
	Shedding of HER2 ectodomain
	Masking of the trastuzumab binding epitope on HER2 p95HER2 expression
Intracellular trafficking and lysosomal degradation	Poor HER2-T-DM1complex internalization
	HER2-T-DM1 recycling to plasma membrane
	Failure of HER2 intracellular trafficking
	Inefficient lysosomal degradation of T-DM1
Drug efflux	MDR1 expression
Other factors
Altered DM1 target	Beta1-tubulin mutation
Autocrine or stromal growth factors	Overexpression of a beta3-tubulin isoform
Modulators of the apoptotic pathway	Microtubule-associated proteins
Activation of cell survival pathways

HER2, human epidermal growth factor receptor-2; T-DM1, trastuzumab emtansine.